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WHO

recommendations
on shorter
MDR-TB regimen
Fuad Mirzayev
WHO Global TB Programme
CNS webinar, 11 July 2016

Main changes in the 2016 recommendations


A shorter MDR-TB treatment regimen is
recommended
Medicines used in the design of conventional
MDR-TB treatment regimens are now regrouped
(Clofazimine/linezolid are now recommended as
core second-line medicines in the MDR-TB
regimen while PAS is an Add-on agent);
MDR-TB treatment is recommended for all
patients with RR tuberculosis, regardless if
isoniazid resistance is confirmed or not
Recommendations are made on the treatment of
children with rifampicin-resistant or MDR-TB
Evidence-informed recommendations on the role
of surgery are now made

Policy formulation process


Transparency; efforts to minimize bias &
conflict; communicate uncertainties
Evidence-informed
Systematic reviews, meta-analysis
Expert groups from broad constituencies
GRADE method to:
assess the certainty of evidence
translate evidence into
recommendations

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July 11, 2016

GRADE evaluation
*Grades of Recommendation Assessment, Development and Evaluation

Clear separation:

Recommendation
strong or conditional/optional/weak (for or
against an intervention)
Benefits and downsides, values and
preferences, impact, resource use
balanced with

Quality of evidence

GRC review cycle 3 to 5 years


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July 11, 2016

Quality of
evidence

Patient
values &
preferences

(High), (Moderate), (Low), (Very low)


Methodological quality of evidence
Likelihood of bias
By outcome and across outcomes

Balance
between
benefits, harms
& burdens

Resource
use

Implications of the strength of a


recommendation for different users

Adapted from Guyatt GH et al. BMJ. 2008, 336(7652):10491051

Certainty of evidence
Certainty
High
Moderate

Low

Very low

Definition
Further research is very unlikely to change our
confidence in the estimate of effect.
Further research is likely to have an important impact
on our confidence in the effect and may change the
estimate.
Further research is very likely to have an important
impact on our confidence in the estimate of effect
and is likely to change the estimate.
Any estimate of effect is very uncertain.
Adapted from Guyatt GH et al. BMJ. 2008 Apr 26,336(7650):924-6

www.who.int/tb/challenges/mdr/short_regimen_use/en/

Current use of shorter MDR-TB regimens


Implementation may be limited to a few sites in a country
Ethiopia, Mongolia, South Africa and Viet Nam also taking part in the STREAM trial

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever
on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its
authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent
approximate border lines for which there may not yet be full agreement. WHO 2012. All rights reserved.

Bangladesh
Benin
Burkina Faso
Burundi
Cameroon
Central African
Republic
Cte dIvoire
DR Congo
Guinea
Niger
Rwanda
Senegal
Swaziland
Uzbekistan

Evidence review for shorter MDR-TB regimen

Meta-analysis of shorter MDR-TB regimens (IPD + aggregated


data). 1,205 patients in Bangladesh, Benin, Burkina Faso,
Burundi, Cameroon, Central African Republic, DR Congo, Niger,
Swaziland, and Uzbekistan
Treatment success versus all other outcomes was reported in
84% (95%CLs: 79%- 87%) of these patients [vs. 62% (95%CLs:
53%-70%) in a comparable selection of MDR-TB patients
treated with a variety of individualized regimens of longer
duration]
In patients who did not complete treatment successfully, 7%
died, 6% were lost to follow up, and 3% had a treatment
failure.
Relapse was incompletely assessed in the studies reviewed (in
2 countries it was assessed at 24 months after treatment; in 1
other at 12 months). Relapse only observed in 3 patients

Shorter MDR-TB regimen (1)


Recommendation
In patients with rifampicin-resistant TB or MDRTB, who have not been previously treated with
second-line drugs and in whom resistance to
fluoroquinolones and second-line injectable
agents has been excluded or is considered highly
unlikely, a shorter MDR-TB regimen of 912
months may be used instead of a conventional
regimen
conditional recommendation, very low certainty in the evidence

Shorter MDR-TB regimen (3)


Main remarks
Standardized regimen; limited modifications permissible
4-6 Km-Mfx-Pto-Cfz-Z-Hhigh-dose-E / 5 Mfx-Cfz-Z-E
Recommendation applies to adults, children, PLHIV
Ideally, patients are tested for resistance to fluoroquinolones and
second-line injectable drugs; not recommended in case of 2nd line
drug resistance, extrapulmonary disease and pregnancy

Lowered costs (<US$1,000 in drug costs/patient)


Monitoring for effectiveness, relapse, and harms (active TB drug
safety monitoring and management (aDSM))
Trials (e.g. STREAM) expected to provide high-certainty evidence

Choosing the treatment regimen in patients


with confirmed RR-/MDR-TB
Do any of the following apply ?

Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDRTB regimen (except isoniazid resistance)
Exposure to >1 second-line medicines in the shorter MDR-TB regimen for >1 month
Intolerance to >1 medicines in the shorter MDR-TB regimen or risk of toxicity (e.g.
drug-drug interactions)
Pregnancy
Extrapulmonary disease

YES

NO
Shorter MDR-TB
regimen

FAILING REGIMEN, DRUG INTOLERANCE,


RETURN AFTER INTERRUPTION >2 MONTHS,
EMERGENCE OF ANY EXCLUSION CRITERION

Individualized
(conventional)
MDR-TB regimens

THANK YOU!